Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)

Yuan Shi, Mochen Cui, Katharina Ochs, Matthias Brendel, Felix L. Strübing, Nils Briel, Florian Eckenweber, Chengyu Zou, Richard B. Banati, Guo Jun Liu, Ryan J. Middleton, Rainer Rupprecht, Uwe Rudolph, Hanns Ulrich Zeilhofer, Gerhard Rammes, Jochen Herms, Mario M. Dorostkar

Research output: Contribution to journalArticlepeer-review

Abstract

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown. Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material. Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.

Original languageEnglish (US)
Pages (from-to)317-329
Number of pages13
JournalNature Neuroscience
Volume25
Issue number3
DOIs
StatePublished - Mar 2022

ASJC Scopus subject areas

  • General Neuroscience

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